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基于UPLC-Q-Orbitrap MS/MS技术研究膝痹宁对KOA模型大鼠的软骨保护效应

张力 刘子修 廖太阳 吴鹏 李晓辰 梅伟 茆军 王培民 张立

张力, 刘子修, 廖太阳, 吴鹏, 李晓辰, 梅伟, 茆军, 王培民, 张立. 基于UPLC-Q-Orbitrap MS/MS技术研究膝痹宁对KOA模型大鼠的软骨保护效应[J]. 南京中医药大学学报, 2023, 39(1): 32-41. doi: 10.14148/j.issn.1672-0482.2023.0032
引用本文: 张力, 刘子修, 廖太阳, 吴鹏, 李晓辰, 梅伟, 茆军, 王培民, 张立. 基于UPLC-Q-Orbitrap MS/MS技术研究膝痹宁对KOA模型大鼠的软骨保护效应[J]. 南京中医药大学学报, 2023, 39(1): 32-41. doi: 10.14148/j.issn.1672-0482.2023.0032
ZHANG Li, LIU Zi-xiu, LIAO Tai-yang, WU Peng, LI Xiao-chen, MEI Wei, MAO Jun, WANG Pei-min, ZHANG Li. Study on Cartilage Protective Effect of Xibining on KOA Model Rats Based on UPLC-Q-Orbitrap MS/MS Technique[J]. Journal of Nanjing University of traditional Chinese Medicine, 2023, 39(1): 32-41. doi: 10.14148/j.issn.1672-0482.2023.0032
Citation: ZHANG Li, LIU Zi-xiu, LIAO Tai-yang, WU Peng, LI Xiao-chen, MEI Wei, MAO Jun, WANG Pei-min, ZHANG Li. Study on Cartilage Protective Effect of Xibining on KOA Model Rats Based on UPLC-Q-Orbitrap MS/MS Technique[J]. Journal of Nanjing University of traditional Chinese Medicine, 2023, 39(1): 32-41. doi: 10.14148/j.issn.1672-0482.2023.0032

基于UPLC-Q-Orbitrap MS/MS技术研究膝痹宁对KOA模型大鼠的软骨保护效应

doi: 10.14148/j.issn.1672-0482.2023.0032
基金项目: 

国家自然科学基金青年科学基金项目 81904224

江苏省领军人才培养资助项目 SLJ0207

江苏省研究生培养创新工程资助项目 KYCX21_1675

详细信息
    作者简介:

    张力, 男, 博士研究生, E-mail: 183718670@qq.com

    通讯作者:

    张立, 男, 主治中医师, 主要从事中医药防治骨关节病的临床与基础研究, E-mail: fsyy00725@njucm.edu.cn

  • 中图分类号: R285.5

Study on Cartilage Protective Effect of Xibining on KOA Model Rats Based on UPLC-Q-Orbitrap MS/MS Technique

  • 摘要:   目的  运用超高效液相色谱-四极杆-静电场轨道阱串联质谱(UPLC-Q-Orbitrap MS/MS)技术分析膝痹宁的药物活性成分, 通过干预膝骨关节炎(KOA)模型大鼠代谢因素探讨膝痹宁软骨保护效应的作用机制。  方法  制备膝痹宁水提物, UPLC-Q-Orbitrap MS/MS技术分析膝痹宁的活性成分。将大鼠分为空白组、KOA组、膝痹宁组, 提取大鼠软骨组织, HE染色、番红O-固绿染色观察组织结构形态; qPCR和Western blot法检测过氧化物酶体增殖物激活受体(PPARγ)、PPARγ辅助激活因子1α(PGC1α)及基质金属蛋白酶(MMP)3、MMP13的mRNA和蛋白表达水平; 取各组大鼠血清完成代谢组学分析。  结果  经鉴定, 膝痹宁含活性成分56种; 组织学切片提示膝痹宁具有软骨保护作用, 并能上调KOA大鼠软骨组织PPARγ、PGC1α的mRNA和蛋白表达水平(P < 0.05, P < 0.01), 降低MMP3、MMP13的mRNA和蛋白表达水平(P < 0.05, P < 0.01);此外, 代谢组学研究发现, 膝痹宁对13种KOA差异代谢物存在干预作用, 涉及10条代谢通路。  结论  膝痹宁具有多种药物活性成分, 其KOA软骨保护效应与药物活性成分对KOA的代谢调控有关。

     

  • 图  1  膝痹宁药液的总离子流图

    Figure  1.  Total ion current diagram of Xibining

    图  2  各组大鼠软骨组织代表性HE染色、番红O-固绿染色

    Figure  2.  The representative HE and Safranin O-Fast Green staining on cartilage tissue of each group

    图  3  各组大鼠软骨组织MMP3、MMP13 mRNA和蛋白相对表达水平比较

    注: A. MMP3、MMP13的相对mRNA表达; B. MMP3、MMP13的代表性蛋白条带; C. MMP3、MMP13的相对蛋白表达; 与空白组比较, **P < 0.01;与KOA组比较, #P < 0.05, ##P < 0.01。x±s, n=5。

    Figure  3.  The relative expression levels of MMP3 and MMP13 in cartilage of rats in each group

    图  4  各组大鼠软骨组织PPARγ、PGC1α mRNA和蛋白相对表达水平比较

    注: A. PPARγ、PGC1α的相对mRNA表达; B. PPARγ、PGC1α的代表性蛋白条带; C. PPARγ、PGC1α的相对蛋白表达; 与空白组比较, **P < 0.01;与KOA组比较, #P < 0.05, ##P < 0.01。x±s, n=5。

    Figure  4.  The relative expression levels of PPARγ and PGC1α in cartilage of rats in each group

    图  5  代表性大鼠血清色谱图

    Figure  5.  The representative chromatogram of rat serum

    图  6  各组大鼠血清的PCA分析

    注: K.KOA组; N.空白组; XBN.膝痹宁组; QC.质控样本

    Figure  6.  PCA analysis of serum in each group

    图  7  OPLS-DA得分图和Permutation test置换检验

    注: K.KOA组; N.空白组

    Figure  7.  OPLS-DA score map and Permutation test

    图  8  代谢差异物的富集分析

    Figure  8.  Enrichment analysis of metabolic difference

    图  9  代谢通路分析

    注: A.烟酸盐和烟酰胺代谢; B.甘油酯代谢; C.乙醛酸和二羧酸的代谢; D.甘氨酸、丝氨酸和苏氨酸代谢、磷酸戊糖途径; E.甘油磷脂代谢; F.氨酰-tRNA生物合成; G.缬氨酸、亮氨酸和异亮氨酸降解、合成; H.嘌呤代谢

    Figure  9.  Metabolic pathway analysis

    表  1  目的基因序列

    Table  1.   Target gene sequence

    目的基因 前引(5'→3') 后引(5'→3')
    MMP3 GGGTGGATGCTGTCTTTG TGCCTTCCTTGGATCTCTT
    MMP13 GGGGAGCCACAGATGAG AACGCTCGCAGTGAAAG
    PPARγ CCTCGAGGACACCGGAGA CACGGAGCTGATCCCAAAGT
    PGC1α GTAGATCCTCTTCAAGATCCTG CATACAAGGGAGAATTGCGA
    GAPDH GTTGTGGCTCTGACATGCT CCCACGGATGCCCTTTAGT
    下载: 导出CSV

    表  2  膝痹宁的活性成分

    Table  2.   The active ingredient of Xibining

    编号 化合物名称 保留时间/min 测得值m/z 离子模式 分子式 主要离子碎片
    1 苹果酸(Malic acid) 0.573 9 133.012 9 [M-H]- C4H6O5 71.007 6, 115.000 0
    2 乌头酸(Aconitic acid) 0.582 6 173.008 0 [M-H]- C6H6O6 85.034 4, 129.027 5
    3 没食子酸(Gallic acid) 0.687 3 169.013 1 [M-H]- C7H6O5 79.014 3, 107.008 5
    4 右旋奎宁酸[D-(-)-quinic acid] 0.712 0 191.055 5 [M-H]- C7H12O 127.044 7, 173.050 9
    5 佛手柑内酯(Bergapten) 0.720 2 215.032 1 [M-H]- C12H8O4 118.046 7, 133.050 5
    6 尿囊素(Allantoin) 0.736 7 157.035 5 [M-H]- C4H6N4O3 69.935 3, 140.004 9
    7 葫芦巴碱(Gynesine) 0.753 3 138.054 8 [M+H]+ C7H7NO2 65.038 9, 78.034 5, 93.057 8
    8 焦儿茶酸(Pyrocatechuic acid) 0.761 5 153.018 2 [M-H]- C7H6O4 108.020 6, 153.017 8
    9 龙胆二糖(Gentiobiose) 0.770 1 360.148 9 [M+NH4]+ C12H22O11 145.049 0, 163.060 1
    10 麦芽三糖(Maltotriose) 0.803 0 527.158 9 [M+Na]+ C18H32O16 185.042 3, 203.051 1, 347.091 1
    11 6-果糖-α-葡糖苷(Isomaltulose) 0.855 7 341.109 1 [M-H]- C12H22O11 71.012 2, 89.022 7, 113.023 3
    12 烟酸(Niacin) 0.945 2 124.039 4 [M+H]+ C6H5NO2 80.049 7, 124.039 1
    13 莽草酸(Shikimic acid) 0.959 2 173.044 6 [M-H]- C7H10O5 67.017 3
    14 松三糖(Melezitose) 0.959 2 503.161 9 [M-H]- C18H32O16 59.012 2, 101.022 9
    15 蜜二糖(Melibiose) 0.988 2 365.105 0 [M+Na]+ C12H22O11 185.042 7, 203.051 3
    16 阿糖尿苷(Aburidine) 1.005 1 243.062 1 [M-H]- C9H12N2O6 110.023 9
    17 次黄嘌呤(Hypoxanthine) 1.541 5 137.045 8 [M+H]+ C5H4N4O 56.943 0, 81.070 1, 90.948 0, 118.942 5
    18 羟基肉桂酸(Hydroxycinnamic acid) 2.353 2 163.039 0 [M-H]- C9H8O3 119.049 3
    19 腺嘌呤(Adenine) 2.609 8 134.046 1 [M-H]- C5H5N5 92.024 2, 107.034 9
    20 香豆素(Cumarin) 3.396 8 147.043 9 [M+H]+ C9H6O2 91.054 2, 119.050 9
    21 阿魏酸(Ferulic acid) 3.491 1 193.049 8 [M-H]- C10H10O4 134.036 6
    22 猪毛菜碱(Salsoline) 3.546 7 194.117 1 [M+H]+ C11H15NO2 70.942 6, 115.054 6, 151.074 4, 177.091 2
    23 泛酸(Pantothenic acid) 3.631 1 220.118 0 [M+H]+ C9H17NO5 72.045 1, 98.023 6, 124.075 9
    24 山栀苷甲酯(Shanzhiside methylester) 3.843 6 405.140 5 [M-H]- C17H26O11 101.023 0, 155.034 1
    25 花椒油素(Xanthoxylin) 3.854 9 197.080 5 [M+H]+ C10H12O4 79.054 4, 90.948 0, 109.065 0, 151.074 1
    26 麦芽糖醇(Maltol) 4.006 7 127.039 0 [M+H]+ C6H6O3 53.039 3, 81.034 2
    27 羟甲香豆素(Hymecromone) 4.025 1 177.054 4 [M+H]+ C10H8O3 77.039 2, 103.054 4
    28 水杨酰胺(Salicylamide) 4.048 5 136.039 1 [M-H]- C7H7NO2 93.033 2, 108.020 5
    29 水杨酸(Salicylic acid) 4.058 1 137.023 0 [M-H]- C7H6O3 81.032 9, 109.028 5
    30 异甘草素(Isoliquiritigenin) 4.095 9 257.080 5 [M+H]+ C15H12O4 119.049 6
    31 刺桐碱(Erysodine) 4.123 1 247.143 6 [M+H]+ C14H18N2O2 60.081 4, 115.054 3, 118.065 3
    32 儿茶酸(Catechin) 4.318 4 289.072 0 [M-H]- C15H14O6 125.023 8
    33 新乌宁碱(Neoline) 4.333 3 438.285 1 [M+H]+ C24H39NO6 72.081 5, 154.122 0
    34 异紫堇定碱(Isocorydine) 4.379 6 342.169 5 [M+H]+ C20H23NO4 58.065 6, 219.078 9
    35 高香草酸(4-Hydroxy-3-methoxyphenylacetic) 4.445 1 165.054 6 [M+H-H2O]+ C9H10O4 83.014 9, 100.024 4, 101.025 9
    36 水杨醛(Salicylaldehyde) 4.545 8 121.028 2 [M-H]- C7H6O2 61.986 7, 92.025 2
    37 丁香醛(Syringaldehyde) 4.843 4 181.049 7 [M-H]- C9H10O4 123.007 5, 166.025 3
    38 黑野樱素(Prunin) 4.883 6 433.113 4 [M-H]- C21H22O10 119.049 0, 271.061 0
    39 羟基喹啉(4-Hydroxyquinoline) 5.197 8 144.044 1 [M-H]- C9H7NO 99.924 2
    40 香草醛(Vanillin) 5.380 9 151.039 0 [M-H]- C8H8O3 136.014 8
    41 滨蒿内酯(Scoparone) 5.516 5 207.065 0 [M+H]+ C11H10O4 84.959 8, 151.075 9
    42 海帕乌头碱(Hipaaconitine) 6.000 0 616.311 4 [M+H]+ C33H45NO10 105.033 2, 338.171 6
    43 邻甲氧基肉桂酸(o-Methoxy cinnamic acid) 6.018 9 161.059 5 [M+H-H2O]+ C10H10O3 79.054 4, 103.054 4, 105.069 9
    44 甘草素(Liquiritigenin) 6.169 1 255.066 4 [M-H]- C15H12O4 135.007 9
    45 肉桂醛(Cinnamyl aldehyde) 6.270 2 133.064 8 [M+H]+ C9H8O 55.018 6, 89.002 2
    46 紫檀素(Angolensin) 6.344 6 271.097 6 [M-H]- C16H16O4 109.028 4, 135.043 5
    47 异欧前胡素(Isoimperatorin) 6.715 4 269.082 1 [M-H]- C16H14O4 254.060 1
    48 大黄素(Emodin) 6.992 4 269.045 4 [M-H]- C15H10O5 197.060 6, 225.053 5
    49 十三烷酸(Tridecanoic acid) 7.973 6 213.185 3 [M-H]- C13H26O2 213.184 0
    50 肉豆蔻酸(Myristic acid) 8.521 0 227.201 4 [M-H]- C14H28O2 195.570 9
    51 甘草酸(Glycyrrhetic acid) 8.926 6 469.332 1 [M-H]- C30H46O4 391.236 1
    52 二十二烷酸(Docosanoic acid) 9.159 6 339.326 5 [M-H]- C22H44O 183.011 2
    53 棕榈酸(Palmitic acid) 9.656 4 187.096 7 [M-H]- C9H16O4 97.064 6, 125.095 4
    54 十七烷酸(Heptadecanoic acid) 9.867 6 269.248 5 [M-H]- C17H34O2 59.012 6
    55 硬脂酸(Stearic acid) 10.536 6 283.263 9 [M-H]- C18H36O2 62.388 1, 78.921 8, 108.558 1, 192.019 4
    56 柠檬酸(Citric acid) 11.652 1 191.018 7 [M-H]- C6H8O7 85.027 7, 111.007 3
    下载: 导出CSV

    表  3  膝痹宁对大鼠血清代谢差异物的调节作用

    Table  3.   Regulation of Xibining on serum metabolic differences in rats

    编号 名称 主要二级碎片信息 KOA组/空白组 KOA组/膝痹宁组
    Fold Change 校正P Fold Change 校正P
    1 左旋肉碱(Levocarnitine) 57.034 1, 121.091 7 0.349 7 0.000 1 0.352 1 0.000 1
    2 甘油醛(Glyceraldehyde) 52.332 4, 72.991 4 0.460 0 0.004 2 0.605 5 0.018 0
    3 谷氨酸(Glutamic acid) 58.028 2, 74.588 8 0.535 1 0.000 2 0.629 7 0.004 6
    4 脯氨酸(Proline) 66.033 3, 71.012 1 0.554 2 0.000 1 0.594 7 0.000 1
    5 亮氨酸(Isoleucine) 69.070 5, 90.951 3 0.587 4 0.000 1 0.583 6 0.000 3
    6 异亮氨酸(DL-Isoleucine) 55.935 3, 72.937 8 0.590 1 0.000 1 0.561 4 0.000 1
    7 鸟嘌呤(Guanine) 56.965 4, 82.065 0 0.609 5 0.000 1 0.675 1 0.003 9
    8 天冬酰胺(Asparaginate) 88.027 3, 98.025 1 0.638 5 0.000 2 0.638 5 0.000 1
    9 半乳糖(Galactose) 60.026 4, 113.021 7 1.415 5 0.025 6 1.362 6 0.002 7
    10 色氨酸(Tryptophan) 59.012 2, 85.027 6 1.486 1 0.023 4 1.704 7 0.000 5
    11 甲基烟酰胺(Methylnicotinamide) 56.944 2, 93.069 2 1.710 0 0.013 3 1.772 6 0.001 1
    12 缬氨酸(Valine) 53.041 8, 98.623 6 2.044 7 0.000 1 1.675 3 0.005 4
    13 硬脂酸(Octadecanoic acid) 78.780 7, 104.813 3 2.118 7 0.041 8 1.929 6 0.001 2
    下载: 导出CSV

    表  4  代谢通路分析

    Table  4.   Metabolic pathway analysis

    代谢通路 P FDR Impact
    嘌呤代谢(Purine metabolism) 0.000 1 0.000 1 0.012 8
    缬氨酸、亮氨酸和异亮氨酸降解(Valine, leucine and isoleucine degradation) 0.000 1 0.000 1 0.000 1
    缬氨酸、亮氨酸和异亮氨酸合成(Valine, leucine and isoleucine biosynthesis) 0.000 1 0.000 1 0.000 1
    氨酰-tRNA生物合成(Aminoacyl-tRNA biosynthesis) 0.000 1 0.000 1 0.000 1
    甘油磷脂代谢(Glycerophospholipid metabolism) 0.000 3 0.000 7 0.000 1
    烟酸盐和烟酰胺代谢(Nicotinate and nicotinamide metabolism) 0.013 3 0.021 0 0.138 1
    甘油酯代谢(Glycerolipid metabolism) 0.021 0 0.021 0 0.093 5
    乙醛酸和二羧酸的代谢(Glyoxylate and dicarboxylate metabolism) 0.021 0 0.021 0 0.079 4
    甘氨酸、丝氨酸和苏氨酸代谢(Glycine, serine and threonine metabolism) 0.021 0 0.021 0 0.024 2
    磷酸戊糖途径(Pentose phosphate pathway) 0.021 0 0.021 0 0.000 1
    下载: 导出CSV
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出版历程
  • 收稿日期:  2022-05-10
  • 网络出版日期:  2023-01-18
  • 发布日期:  2023-01-10

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